The Action of Peroxyl Radicals, Powerful Deleterious Reagents, Explains Why Neither Cholesterol Nor Saturated Fatty Acids Cause Atherogenesis and Age-Related Diseases

[Todd Allen]

The Action of Peroxyl Radicals, Powerful Deleterious Reagents, Explains Why Neither Cholesterol Nor Saturated Fatty Acids Cause Atherogenesis and Age-Related Diseases
http://sci-hub.tw/https://doi.org/10.1002/chem.201404383

10. Conclusion
The most important source for the generation of radicals was previously assumed to be superoxide. This belief was based on the experiments in which tissue was homogenized and centrifuged to isolate mitochondria or other organelles (section 8). Since homogenization abundantly produces LOOC radicals, it is questionable if superoxide is generated at all in the postulated leakage process (section 8, reference [136]) but rather in a cyclic reaction sequence (section 6.9, references [120, 121]; Figure 9) producing protonated superoxide radicals but not superoxide in a completely different pathway. We assume that besides radiation, the only source of radicals is a multistep processes. First, tissues are stimulated by inside or outside events (section 2.2). This stimulation activates a great number of catabolic enzymes. In the first step, phospholipases liberate free fatty acids from the glycerides (section 3.1) followed by their transformation to lipid hydroperoxides by lipoxygenases (section 3.2). Under severe molecular stress (section 3.3), for instance microbial attack or by mechanical tissue disruption (homogenization), the process proceeds to a third step by liberating bivalent metal ions at the active center of the enzyme (section 3.3) initiating a Fenton reaction with the generation of PUFA-derived LOOC radicals (section 4).

Previously it was presumed that atherogenesis is caused by an accumulation of cholesterol and saturated fats (section 5.1, references [45, 66, 89]). This view was based on the observation that a diet rich in cholesterol and saturated fatty acids induces atherogenesis (section 5.1). A diet rich in PUFAs of plant origin could reduce cholesterol level (section 5.1). However, it must be noted that preparation of the diet for these experiments involved a homogenization process (section 6.2.4). Thus, the fact was overlooked that homogenization as well as heating of food could produce large amounts of peroxyl radicals that react with cholesterol to give toxic cholesterol oxides (section 6.2.2), that contribute to the induction of atherogenesis. Therefore, a decrease in cholesterol level is not a factual situation but is a self-deception. Since peroxyl radicals do not only react with cholesterol, but with other biomolecules too, it is expected that these changes all together contribute to induction of atherogenesis (see below). These changes increase by aging.

The deduction that polyunsaturated fatty acids protect against atherogenesis is based on the feeding experiments in which the food was homogenized and thus produced cholesterol oxides, which simulated a decrease in cholesterol (section 6.3). Yet another conviction that w-3 fatty acids protect against heart diseases is not true because the protection by the marine food is caused by powerful antioxidants like F-acids (section 6.7). Equally the assertion that saturated fats are atherogenic must be revised: saturated fatty acids withstand oxidative degradation and therefore cannot induce atherogenesis (section 6.3). This warrants health guidelines for a correction.

The action of LOOC radicals is not only restricted to cholesterol oxidation, but it also generates a great variety of other toxic lipid-derived molecules such as a,b-unsaturated carbonyl compounds (section 9.1). LOOC radicals can attack all kinds of biomolecules (sections 6 and 9) such as proteins and carbohydrates that are oxidized to their corresponding carbonyl compounds (section 6.9.2). Even if we accept that toxic compounds are generated only in minuscule amounts and can be steadily removed from the metabolism, their relentless formation may have an accumulative effect that outstrips a threshold limit. If this process regenerates ceaselessly, we speculate that aging and age-related diseases start to advance.

Although the generation of toxic compounds has grave consequences, it seems much more serious when radicals act at the molecular/cellular level and randomly change the structure of biomolecules (section 9.5). In this case, proteins, vitamins and enzymes lose their catalytic activities. One way to decrease deleterious effects of radicals is the circumvention/evasion of overheating/homogenization of food.

Thus, the most important message of this Review is that toxic compounds are not only undetected in food but also LOOC radicals are generated as intermediate elements. These have the ability to obliterate important molecules indispensable for life such as enzymes that are degenerated by manipulation of food. Thus, we have tried to demonstrate that through radical attack (sections 6 and 9), not only specific single compounds can become toxic but also a random attack of radicals on biomolecules has serious consequences. So far this important aspect of free-radical chemistry has not been genuinely addressed as a possibility to explain the onset of chronic diseases. This prospect must be seriously considered in future research that may open many new avenues in health practices.

[TomBAvoider]

If the headline is true that neither cholesterol nor saturated fat cause atherosclerosis and CVD, then why is it that higher serum LDL is associated strongly with CVD? And why in cases of familial hypercholesterolemia, you have massive heart disease and atherosclerosis and early deaths? And conversely, why do people with genetically low cholesterol (based on those people PCSK9 anti-cholesterol drugs were developed) have virtually zero atherosclerosis and CVD - and why those PCSK9 drugs which mimic those genetic conditions, when given to people who have otherwise high cholesterol show drastic improvement? 

High LDL is pretty much established as causative of CVD and atherosclerosis. It may not be the *only* cause, and it may not *always* result in CVD, but it's pretty well established to definitely be *a* cause - thus directly contradicting the headline claim of cholesterol *not* being a cause of CVD. 

Saturated fat, has been proven to raise LDL levels - this is pretty uncontroversial, it's a proven effect. It also may raise HDL, but not nearly as much as LDL, being a net negative. There's speculation that it raises larger LDL particles and not smaller, but *all* LDL particles, including the large ones have been associated with CVD. Therefore it seems a bit of a semantic game to say it "doesn't cause" CVD. Strictly speaking guns don't kill people, bullets do - but are we therefore going to exonerate guns? That's how I feel about cholesterol and SFA - we can argue about downstream effects and what causes what proximally, but it's a distinction without much difference. Although I suppose one could try to finesse things with drugs - and hey, Chris Rock had a whole bit about making bullets cost $5K, which would cause gun violence to go down without the necessity of dealing with guns, so there's precedent, I suppose.

In any case, I feel about this as I feel about a lot of the hype when new findings are announced - it's a pity that they are overselling it with wrong and misleading statements. There may be such radicals involved in CVD as they claim, but that does *not* mean cholesterol and SFA are no longer causative agents.

[mikeccolella]

https://www.physiology.org/doi/full/10.1152/japplphysiol.00345.2006?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed&

Tom excellent and on the mark. Cholesterol as a risk factor is incontrovertible but like climate change deniers it still persists that cholesterol has nothing to do with it. Also the fact that fat tends to raise Hdl has been often hailed as a plus see the above. Long ago it was shown that fats cripple the positive effects of hdl

[mccoy]

My take is that if Dr. Peter Attia, a lowcarber himself, reasons that LDL and Trygs must be kept in the lower percentiles for longevity, then SAFAs must be potentially hazardous, unless the individual can show that hir lipid panel remains good (at least LDL-p and tryglicerides, if we are deniers about other parameters). Some guys tolerate fats pretty well, others simply don't.

[Todd Allen]

Mccoy, if you go back and listen to Dr. Attia closely his position is high LDL-p is problematic in the context of compromised endothelium but high LDL does not cause the compromised endothelium.  Since evaluating endothelial health accurately is not currently possible short of an autopsy he believes it is prudent to maintain low LDL as that is something we can readily track.

[mccoy]

Well, that's an example of application of the prudential principle... The decisional aspect remains: LDL-p and trygs in the low percentiles to keep CV hazard low.

[mikeccolella]

23 hours ago, mccoy said:

My take is that if Dr. Peter Attia, a lowcarber himself, reasons that LDL and Trygs must be kept in the lower percentiles for longevity, then SAFAs must be potentially hazardous, unless the individual can show that hir lipid panel remains good (at least LDL-p and tryglicerides, if we are deniers about other parameters). Some guys tolerate fats pretty well, others simply don't.

it’s not just about lipid panels. Fats interfere with hdl processing see the above article I posted. Also high fat diets corrupt the vasodilation potential which leads to endothelial compromise. Compromised endothelium becomes more vulnerable to oxidized ldl particles. Heart disease is a result of a highly complex physiological process. There are numerous factors at play including genetics. That is why these myths about cholesterol not being a factor persist.